Many forms of human cancer are treated by surgical resection, chemotherapy, and/or radiation. Surgery provides significant survival advantages for a broad range of tumor types and cures approximately 45% of all patients with solid tumors [1]. To successfully treat a patient with surgery, the surgeon must remove the entire tumor at the time of surgery including the primary tumor, draining lymph nodes that may contain tumor cells and small adjacent satellite nodules. Statistical data indicate that complete resection is the single most important predictor of patient survival for almost all solid tumors [2]. In lung, breast, prostate, colon, and pancreatic cancers, a complete resection has a 3-5 fold improvement in survival as compared to partial resection [3-8]. Recent advances in computed tomography (CT), positron emission tomography (PET), and hybrid techniques (such as CT/PET) have greatly improved tumor detection and surgical planning [9,10], but these modalities do not provide real-time intra-operative assistance. Intra-operative magnetic resonance imaging (MRI) can assist in surgical resection of tumors, but it is time consuming and substantially adds to the length of surgery, anesthesia time, and financial costs [11]. Intra-operative sonography has also shown potential for detection of breast cancer but has limited sensitivity for detection of masses less than 5 mm [12]. Faced with these difficulties, optical technologies based on cellular imaging, native fluorescence, and Raman scattering have gained attention for tumor detection and diagnosis [13-17]. In particular, the level of autofluorescence from collagen, nicotinamide adenine dinucleotide (NADH), and flavin adenine dinucleotide (FAD) has been associated with malignancy in head and neck cancer [17-19]. Chemical and biochemical changes have been measured by laser Raman spectroscopy for margin assessment of breast cancer [15, 20] and for noninvasive detection of cervical dysplasia during routine pelvic exams [21]. Small changes in cellular biochemistry may translate into spectroscopic differences that are measurable with fluorescence or Raman scattering. However, tumors are highly heterogeneous in their molecular and cellular compositions [22], and biochemical differences in malignant and benign tissues are subject to natural variations in patient physiology and pathology [23]. Thus, autofluorescence and intrinsic Raman measurements often lead to unacceptable false-positive rates for benign tissues and unacceptable false-negative rates for malignant tissues [24, 25].
Due to tissue scattering and blood absorption, optical methods have relatively limited penetration depths [26, 27]. For intra-operative applications, however, the lesions are surgically exposed and can be brought in close proximity to the imaging device, so they become accessible to optical illumination and detection. A problem in using exogenous contrast agents is that they are often unable to deeply penetrate solid tumors, especially when macromolecules such as monoclonal antibodies or nanoparticles are used [28-30]. For detection of tumor margins during surgery, on the other hand, the agents are detected at the tumor periphery and deep penetration is not required. Similarly, for detection of small and residual tumors, deep penetration is not required because small tumors do not have a high intra-tumoral pressure or a necrotic/hypoxic core, two factors in limiting tumor penetration of imaging and therapeutic agents [28-30].
There is a need for anatomical guidance and rapid pathology to be provided during the diagnostic or therapeutic procedure, to determine if a tumor has been completely resected, such as by verifying that the margin of resected tumor tissue is clear, without having to wait for pathology to process the resected tissue to verify that there are no remaining signs of cancerous growth in the margin.
Therefore, a heretofore unaddressed need still exists in the art to address the aforementioned deficiencies and inadequacies.